Both T cell and B cell immune responses to HCV are being investigated using primarily the chiompanzee model and inbred mice and transgenic mice. T cell studies are continuing in an effort to identify both cytotoxic T cell and helper T cell epitopes. We are studying the proliferative and CTL responses of in chimpanzees infected by a monoclonal virus without detectable quasispecies diversity. This virus was derived from the full length, infectious cDNA clone of the HCV genome. We have inoculated a group of chimpanzees with this virus and are monitoring their immune responses in detail using a perfectly matched set to reagents. As some of these animals clear the virus and recover completely from acute HCV infection and others go on to develop persistent infections, we hope to determine the precise immunologic differences between the recovered and chronic chimpanzees. Utilizing this information, we plan to construct vaccines desgned to induce an immune response similar to that which resulted in viral clearance. We are also investigating the response es in animals that have cleared HCV infections upon reinoculation. Again, we are looking for clues on how to construct a successful vaccine. Animals that recover are known to have brisk T cell responses to a variety of HCV antigens. However, they typically do not develop antibody responses to either of the envelope glycoproteins, E1 or E2 and upon reinoculation with even the same virus as the one that caused the initial infection, the animal can be reinfected. We have immunized such an animal with a with vaccines designe dto induce antibosy to E1/E2 in order to determine if adding that antibody to the immune response that resulted in recovery would produce solid immunity against reinfection. This experiment is ongoing. Mice transgenic for human HLA alleles are being used to model human immune responses to HCV vaccines.